The development of the head and neck, as well as the embryo in general, is the result of sophisticated cellular migrations that form virtually ll of the skeletal, muscular and glandular structures. The mechanism that underlie the initiation, directionality and cessation of cell migrations are poorly understood, despite the fact that they are responsible for some of the most common congenital malformations. During the past few years, my laboratory has identified a novel molecular mechanism for mesenchymal cell interactions with the underlying basal lamina matrix. Results show that cell surface B1,4-galactosyltransferase (Ga1Tase) participate during mesenchymal cell spreading and migration on laminin. GalTase is localized by indirect immunofluorescence to the leading and trailing edges of migrating cells, consistent with its proposed role during spreading and migration. GalTase does not participate during initial adhesion to laminin, which is mediated by distinct laminin receptors, and binding site in laminin has been identified as the E8 domain, and E8's biological activity has been shown to be at least partly dependent upon binding to surface GalTase. Surface GalTase associates with the specific for GalTase. That surface GalTase may function catalytically during cell migration, rather than as a lectin, is shown by the spontaneous galactosylation of laminin matrices by migrating mouse fibroblasts. In an analogous manner, GalTase is expressed on the growth cone of developing neurites, where it mediates neurite initiation and outgrowth on laminin. Recent advances in the molecular biology of surface GalTase now allows one to increase or decrease the expression of surface GalTase, which leads to predictable consequences on lamellipodia formation, cell migration and neurite outgrowth on laminin. Finally, surface GalTase appears to function in vivo, as shown by the ability of anti-GalTase antibodies of inhibit the migration of neural crest cells in vivo. These studies define a novel molecular mechanism for cell process formation on laminin. These results lead to the next series of Specific Aims that we will pursue during the coming funding period, which are grouped into two major classes: analysis of GalTase association with the cytoskeleton and analysis of surface GalTase function during morphogenesis in vivo.
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